Summary:

This is the study to test combination regimen of Nilotinib and Ruxolitinib therapy for the
treatment of patients with Philadelphia positive chronic myeloid leukemia (CML) or acute
lymphoblastic leukemia (ALL) who is resistant to multiple tyrosine kinase inhibitor therapies
with BCR-ABL kinase inhibition activity. Ruxolitinib is a tyrosine kinase inhibitor blocking
alternative pathway independent of BCR-ABL mediated pathway, thus having a potential to
overcome tyrosine kinase inhibitor resistance in Philadelphia positive CML or ALL patients.
Phase I study will be conducted to define a recommended phase II dose (RPTD) and phase II
study will examine the hypothesis that combinational approach will increase response rate of
resistant CML/ALL patients, thus evaluating efficacy of the combination regimen.

Trial Description

Primary Outcome:

Phase I: Maximum Tolerated Dose (MTD)

Phase II: Major cytogenetic response

Secondary Outcome:

Phase I: complete hematologic response

Phase I: major cytogenetic response

Phase I: Safety and tolerability

Phase II: complete hematologic response

The purpose of this study is to find out if multiple tyrosine kinase inhibitor resistant
chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) can be treated with
combination approach of Nilotinib with Ruxolitinib which may block alternative pathway
besides BCR-ABL kinase inhibition in Ph positive leukemia, esp against JAK2-STAT5 pathway.
First step is to define the dose of Ruxolitinib with fixed dose of Nilotinib which had been
approved at the dose of 400mg bid for imatinib failed CML.
During phase I part of the study,dose escalations will be decided on the basis of DLTs
observed hence the exact sample size could not be predicted with certainty but will range
between 9-12 patients. Three patients will be enrolled per dose level. Accordingly 9 patients
are expected to be enrolled. If a DLT is observed, 3 more patients will be enrolled at the
dose level in which the DLT occurred.
The study will be conducted at multiple sites across Canada and enrollment will be
competitive. Once 3 patients are enrolled in a cohort, that dose level will be closed to
enrollment until safety assessment of the 3 subjects is performed at the end of cycle 1. This
procedure will be performed for each dosing cohort. Patients will be assigned to a dose level
based on authorization from the sponsor in collaboration with Ozmosis Research Inc.
For the phase II part of the study, once the RPTD has been established in the phase I portion
of this trial, the phase II will begin. The phase II portion will be a two-stage, single arm,
unblinded study investigating the potential efficacy of the combination of Ruxolitinib and
Nilotinib.
A maximum of 20 patients will be accrued in the phase II portion. Those patients treated in
the phase I portion of this trial at the RPTD will be included in the analysis of the Phase
II study.